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Browsing by Subject "Small GTPases"

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    Protein prenylation in the pathogenesis of Alzheimer’s Disease and its therapeutic potential
    (2021-06) Jeong, Angela
    With the unprecedented growth of senior population, Alzheimer’s disease (AD) has risen in prevalence to approximately 50 million people afflicted worldwide. While the molecular mechanisms underlying the AD pathogenesis have yet to be elucidated, emerging evidence suggests that a key posttranslational lipid modification of proteins, called prenylation, may play an important role in the pathogenesis of AD. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), are synthesized from mevalonate in the cholesterol biosynthesis pathway, and the attachment of these lipid prenyl groups is catalyzed by farnesyltransferase (FT) and geranylgeranyl transferases (GGTs), respectively. Once prenylated, proteins localize to cell membranes, where they interact with downstream effectors, and regulate various cellular processes. Multiple lines of evidence have shown that modulation of protein prenylation affects AD neuropathology. To investigate the contribution of each prenylation pathway to AD pathogenesis, our laboratory previously generated the transgenic AD model mice (APP/PS1) with systemic haplodeficiency of FT or GGT. While haplodeficiency of either FT or GGT reduced Aβ deposition and neuroinflammation, only FT haplodeficiency rescued cognitive deficits, suggesting distinct functions of the two prenylation pathways. To follow up on the previous work, my dissertation research is aimed to: 1) investigate the AD pathology-associated changes in prenylation; 2) elucidate the role of neuronal FT in the AD pathogenesis; 3) identify prenylation substrates involved in AD pathogenesis, which can be potentially targeted for therapeutic development. Studies with postmortem human brain tissue samples from two cohorts found that FT levels and the farnesylation of H-Ras were significantly elevated in the brains with AD. In line with this evidence from human samples, neuronal FT deletion attenuated memory impairment and mitigated the Aβ levels by reducing its production as well as normalizing the heightened mTORC1 activity in APP/PS1 mice. Finally, experiments employing a novel prenylomic profiling approach identified proteins whose prenylations were significantly upregulated in APP/PS1 mice compared to WT controls. Taken together, the findings from my dissertation research indicate that aberrant upregulation of protein farnesylation contributes to the pathogenic process of AD, and targeting protein farnesylation and/or downstream signaling pathways of farnesylated proteins may confer therapeutic benefits against AD.